Prader-Willi syndrome is a neurobehavioral disorder characterized by infantile hypotonia, short stature, and neonatal failure to thrive followed by obsessive-compulsive behavior, hyperphagia, and obesity. PWS results from loss of expression of several imprinted genes located at 15q11-13 and can arise from maternal 15q disomy, paternal deletion of a group of PWS genes, or paternal microdeletions removing an imprinting center (IC) necessary for paternal gene expression. We previously created a PWS mouse model by targeted deletion of the IC. Pups bearing a paternal IC deletion exhibit a failure to thrive inevitably leading to death in the first postnatal week. In the previous funding period, we found that death of IC deletion pups born to mothers of some strains survive, finally providing an opportunity to investigate the role of PWS genes in adult, as well as fetal and postnatal stages. The etiology of early postnatal death in PWS-IC deletion mice is complex. While failure to thrive is one cause, respiratory problems caused by Necdin deficiency is also an important factor. Additionally, we have found evidence for multi-locus failure to thrive. In specific aim 1, we will use complementation by BAC transgenes expressing groups of PWS genes to identify loci involved in failure to thrive and to confirm the role of Necdin in early postnatal death in PWS mouse models. Obesity and underlying hyperphagia are salient aspects of PWS. Specific aim 2 proposes to explore various conditions to develop obesity in surviving adult PWS mice, and investigate the roles of PWS genes in progression to obesity. A number of imprinted genes are known to be involved in fetal growth. We have recently found that IC deletion embryos have decreased fetal growth and that some PWS genes are expressed in the placenta. In specific aim 3, we will combine existing PWS models and BAC transgene complementation to test the role of subsets of PWS genes in placental development. We anticipate that this research will significantly contribute to understanding the roles of individual genes in complex PWS traits, refine mouse models of the disease, and provide new insights into growth and obesity.